This application proposes to investigate the function and role(s) of NAC-1. NAC-1 is a member of the POZ family of proteins and is present in the mammalian central nervous system (CNS). NAC-1 mRNA levels are increased in the nucleus accumbens of the rat CNS three weeks after chronic cocaine self administration. Interruption of NAC-1 expression via microinjection of antisense oligonucleotides into the rat nucleus accumbens augmented the locomotor responses to acute and chronic treatment, supporting the hypothesis that NAC-1 regulates the function of neurons in the nucleus accumbens that contribute to the behavioral sensitization and cocaine self-administration. The proposed molecular and behavioral studies are designed to understand how alterations in NAC-1 expression affect cocaine associated behaviors. The Specific Aims will: Aim 1: study NAC-1 binding to specific DNA sequences and other proteins and examine the effects of cocaine treatment on these interactions in the CNS; Aim 2: demonstrate the intracellular location (in vitro studies) and regional CNS distribution (in vivo studies) of NAC-1 protein before and after cocaine treatment; Aim 3: study the effects of diminished NAC-1 levels in the nucleus accumbens on the behavioral effects of acute cocaine and cocaine self- administration in the rat. Motor behavior or the rate of reinstatement of self administration will be measured after antisense oligonucleotide injection; Aim 4: determine the behavioral effects of acute cocaine after over- expression of NAC-1 protein in the nucleus accumbens via injection of a recombinant adeno virus vector that contains the NAC-1 cDNA. Repeated cocaine use leads to persistent molecular and behavioral changes. NAC-1 is one mRNA that demonstrates a long-term adaptation to cocaine use. Results from studies of NAC-1 function in the rat may be helpful in future studies of human subjects who abuse cocaine.